The present invention relates to compounds which are inhibitors of retinoic acid-related orphan receptor γt (RORγt) activity and which are therefore of use in the treatment of immune-mediated diseases, including autoimmune diseases, and inflammatory conditions. The invention also relates to methods of preparing the compounds and pharmaceutical compositions containing them.
RORγt is known to play a central role in immune system development since it both regulates development of T cells in the thymus and differentiation of effector T cells in the periphery. RORγt is also required for the differentiation of pro-inflammatory Th17 cells (Ivanov et al, Cell, 126, 1121-1133, 2006). Small molecule inhibitors of RORγt inhibit the differentiation of human Th17 cells in vitro and reduce Th17 cell numbers and disease activity in animal models of autoimmune disease (Huh et al., 2011, Nature 472:486-490). RORγ is also involved in the development of other pathogenic immune cells include type 3 innate lymphoid cells (ILCs). Interleukin 23 activates ILCs in a RORγt-dependent manner (Luci et al., 2008; Buonocore et al., 2010, Nature 464:1371-1375) and these cells contribute to experimental colitis and are present in the inflamed intestine of patients with IBD (Buonocore et al., 2010; Geremia et al., 2011, J Exp Med 208:1127-1133).
It has been demonstrated that Th17 cells and their products, IL17A, IL-17F, IL-21 and IL-22, are associated with the pathology of various inflammatory and autoimmune disorders, in particular, chronic inflammatory diseases such as psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, ankylosing spondylitis, systemic lupus erythematosus and lung diseases including severe asthma, chronic obstructive pulmonary disease and cystic fibrosis.
Some antagonists of RORγt are known and, for example, WO 2012/106995A1, WO 2014/026327, WO 2014/026328, WO 2014/026329, WO 2014/026330, WO 2014/028589, WO 2014/028592, WO 2014/028597 and WO 2014/028600 all relate to compounds which are said to have RORγt inhibiting activity.